White matter microstructural differences in underweight adolescents with anorexia nervosa and a preliminary longitudinal investigation of change following short-term weight restoration.

PURPOSE: Anorexia nervosa (AN) affects approximately 2.9% of females and has the highest mortality rate among all psychiatric disorders. Despite several advances, the neurobiology of this disorder is still not well understood. Several studies have reported abnormalities in the white matter, but it is not know if these are disease-related or secondary to undernutrition. This study aimed to further our understanding of white matter pathology using diffusion-weighted imaging in underweight adolescents with AN, and to examine changes occurring after short-term weight restoration. METHODS: Analyses were conducted on diffusion-weighted imaging from 24 female adolescents with AN and 17 age- and gender-matched healthy controls (HC), aged 14-19 years. Groups were compared on fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) using tract-based spatial statistics analysis and DTI measures were correlated with eating disorder examination questionnaire (EDE-Q) subscales and body mass index (BMI). Preliminary repeated-measure analyses were also conducted on eight participants after short-term weight restoration (median 41 days). RESULTS: Widespread increases in MD of up to 9% were found in underweight AN relative to HC, particularly in the corpus callosum. This was associated with both increased AD and RD, suggestive of dys- or de-myelination. There were no significant group differences in FA, and no significant correlations between DTI measures, BMI or EDE-Q subscale score. Weight restoration therapy significantly reduced MD, to levels significantly lower than HC, but did not consistently alter FA across individuals. CONCLUSIONS: White matter microstructure is significantly altered in female adolescents with AN, with preliminary longitudinal data suggesting that it may be reversible with short-term weight restoration. LEVEL OF EVIDENCE: Level III: evidence obtained from well-designed cohort or case-control analytic studies.

Effects of starvation and short-term refeeding on gastric emptying and postprandial blood glucose regulation in adolescent girls with anorexia nervosa.

Postprandial glucose is reduced in malnourished patients with anorexia nervosa (AN), but the mechanisms and duration for this remain unclear. We examined blood glucose, gastric emptying, and glucoregulatory hormone changes in malnourished patients with AN and during 2 wk of acute refeeding compared with healthy controls (HCs). Twenty-two female adolescents with AN and 17 age-matched female HCs were assessed after a 4-h fast. Patients were commenced on a refeeding protocol of 2,400 kcal/day. Gastric emptying (13C-octanoate breath test), glucose absorption (3-O-methylglucose), blood glucose, plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin, C-peptide, and glucagon responses to a mixed-nutrient test meal were measured on admission and 1 and 2 wk after refeeding. HCs were assessed once. On admission, patients had slower gastric emptying, lower postprandial glucose and insulin, and higher glucagon and GLP-1 than HCs ( P < 0.05). In patients with AN, the rise in glucose (0-30 min) correlated with gastric emptying ( P < 0.05). With refeeding, postprandial glucose and 3-O-methylglucose were higher, gastric emptying faster, and baseline insulin and C-peptide less ( P < 0.05), compared with admission. After 2 wk of refeeding, postprandial glucose remained lower, and glucagon and GLP-1 higher, in patients with AN than HCs ( P < 0.05) without differences in gastric emptying, baseline glucagon, or postprandial insulin. Delayed gastric emptying may underlie reduced postprandial glucose in starved patients with AN; however, postprandial glucose and glucoregulatory hormone changes persist after 2 wk of refeeding despite improved gastric emptying. Future research should explore whether reduced postprandial glucose in AN is related to medical risk by examining associated symptoms alongside continuous glucose monitoring during refeeding.

Grey matter volume in adolescents with anorexia nervosa and associated eating disorder symptoms.

Anorexia nervosa (AN) is a mental health disorder of complex aetiology. Previous neuroimaging studies have found consistent global reductions in global grey matter volume of underweight girls with AN; however, differences in regional grey matter volumes are less consistent. The aims of this study were to investigate grey matter regional volumes of adolescent girls with AN before and after weight recovery and the relationship of any changes with clinical characteristics. We collected high-resolution T1-weighted images from 26 underweight girls with AN before weight gain and 20 healthy control volunteers. Clinical features were assessed using the Eating Disorder Examination Questionnaire. AN subjects displayed reduced grey matter volumes in the insula, amygdala, prefrontal, hippocampal and cingulate cortices and the precuneus, relative to healthy controls. In a subset of 10 AN subjects who were followed after weight recovery, grey matter volumes increased to near-control levels in the orbito- and medial prefrontal, insular, left hippocampal and mid- and posterior cingulate cortices and precuneus. The recovery of the right anterior thalamus and the left orbitofrontal cortex was correlated with improvements in eating concerns and shape concerns, respectively. However, large parts of the anterior cingulate cortex, caudate nuclei and right hippocampus did not display any grey matter recovery following a short-term of treatment. These results show that in adolescents with AN, some brain regions display marked recovery in grey matter volume following weight recovery, whereas others do not, considering grey mater recovery possibly linked to symptom improvement.

A systematic review of approaches to refeeding in patients with anorexia nervosa.

OBJECTIVE: Given the importance of weight restoration for recovery in patients with anorexia nervosa (AN), we examined approaches to refeeding in adolescents and adults across treatment settings. METHODS: Systematic review of PubMed, PsycINFO, Scopus, and Clinical Trials databases (1960-2015) using terms refeeding, weight restoration, hypophosphatemia, anorexia nervosa, anorexia, and anorexic. RESULTS: Of 948 screened abstracts, 27 met these inclusion criteria: participants had AN; reproducible refeeding approach; weight gain, hypophosphatemia or cognitive/behavioral outcomes. Twenty-six studies (96%) were observational/prospective or retrospective and performed in hospital. Twelve studies published since 2010 examined approaches starting with higher calories than currently recommended (≥1400 kcal/d). The evidence supports 8 conclusions: 1) In mildly and moderately malnourished patients, lower calorie refeeding is too conservative; 2) Both meal-based approaches or combined nasogastric+meals can administer higher calories; 3) Higher calorie refeeding has not been associated with increased risk for the refeeding syndrome under close medical monitoring with electrolyte correction; 4) In severely malnourished inpatients, there is insufficient evidence to change the current standard of care; 5) Parenteral nutrition is not recommended; 6) Nutrient compositions within recommended ranges are appropriate; 7) More research is needed in non-hospital settings; 8) The long-term impact of different approaches is unknown; DISCUSSION: Findings support higher calorie approaches to refeeding in mildly and moderately malnourished patients under close medical monitoring, however the safety, long-term outcomes, and feasibility outside of hospital have not been established. Further research is also needed on refeeding approaches in severely malnourished patients, methods of delivery, nutrient compositions and treatment settings.

Exploring bi-directional impacts of Lisdexamfetamine dimesylate on psychological comorbidities and quality of life in people with Binge Eating Disorder.

BACKGROUND: Lisdexamfetamine dimesylate (LDX) has demonstrated safety and efficacy for treatment of Binge Eating Disorder (BED). However, to date, trials have not included participants with co-occurring psychiatric disorders. This study explores how LDX affects eating disorder psychopathology, symptoms of common psychiatric comorbidities of BED (ADHD, depression, anxiety), and psychological quality of life, in people with moderate to severe BED. METHODS: These are secondary analyses of an open-label LDX trial conducted in 41 adults (18-40 years) over eight-weeks. Participants received LDX titrated to 50 or 70 mg. Clinical assessments and self-report questionnaires were conducted at baseline and 8-week follow-up. RESULTS: Eating disorder psychopathology and psychological quality of life improved after 8-weeks of LDX. No significant group-level changes in depression, anxiety or ADHD severity scores were observed. However, the majority within the small subsets with elevated depression and ADHD symptoms experienced reduced depressive and inattentive symptom severity, respectively. CONCLUSIONS: We provide proof-of-concept evidence that LDX may provide broader psychological benefits to individuals with BED, beyond reducing their BE frequency. Effects of LDX on anxiety should be monitored closely by clinicians. Early indications suggest that LDX may be effectively used in people with BED, with and without co-occurring psychiatric conditions, however tolerability may be lower in highly complex cases. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (anzctr.org.au) #ACTRN12618000623291.

Lisdexamfetamine dimesylate (LDX) has been shown to reduce binge eating frequency among those with Binge Eating Disorder (BED). However, little is known about how LDX affects symptoms of common co-occurring conditions (ADHD, depression, anxiety) and mental health more broadly. In this study, 41 people with BED received an 8-week course of LDX and their symptoms were monitored before and after treatment. Overall, people experienced a robust improvement in eating disorder psychopathology and psychological quality of life. For those with higher levels of depression and ADHD, LDX had the additional benefit of improving depressive symptoms and inattentive symptom severity, respectively. The effect of LDX on anxiety symptoms appears to be more complex, with an equal proportion of people experiencing a decrease or an increase in anxiety over the course of treatment. Those who experienced reductions in anxiety during treatment tended to have greater concurrent reductions in binge eating frequency. This study provides preliminary evidence that for people with BED, LDX may be effective at improving co-occurring symptoms of eating disorder psychopathology and psychological well-being, and potentially ADHD and depression symptoms when present at an elevated level. More research is needed among a larger sample to verify these findings.

Functional Connectivity Mechanisms Underlying Symptom Reduction Following Lisdexamfetamine Treatment in Binge-Eating Disorder: A Clinical Trial.

Background: Speculation exists as to whether lisdexamfetamine dimesylate (LDX) acts on the functional connectivity (FC) of brain networks that modulate appetite, reward, or inhibitory control in binge-eating disorder (BED). Better insights into its action may help guide the development of more targeted therapeutics and identify who will benefit most from this medication. Here, we use a comprehensive data-driven approach to investigate the brain FC changes that underlie the therapeutic action of LDX in patients with BED. Methods: Forty-six participants with moderate to severe BED received LDX titrated to 50 or 70 mg for an 8-week period. Twenty age-matched healthy control participants were also recruited. Resting-state functional magnetic resonance imaging was used to probe changes in brain FC pre- and post treatment and correlated with change in clinical measures. Results: Ninety-seven percent of trial completers (n = 31) experienced remission or a reduction to mild BED during the 8-week LDX trial. Widespread neural FC changes occurred, with changes in default mode to limbic, executive control to subcortical, and default mode to executive control networks associated with improvements in clinical outcomes. These connections were not distinct from control participants at pretreatment but were different from control participants following LDX treatment. Pretreatment connectivity did not predict treatment response. Conclusions: FC between networks associated with self-referential processing, executive function, and reward seem to underlie the therapeutic effect of LDX in BED. This suggests that LDX activates change via multiple systems, with most changes in compensatory networks rather than in those characterizing the BED diagnosis.

Effect of a prescriptive dietary intervention on psychological dimensions of eating behavior in obese adolescents.

BACKGROUND: Overweight adolescents are more likely to have dysfunctional eating behaviours compared to normal weight adolescents. Little is known about the effects of obesity treatment on the psychological dimensions of eating behavior in this population. OBJECTIVE: To examine the effects of a prescriptive dietary intervention on external eating (eating in response to food cues, regardless of hunger and satiety), emotional eating and dietary restraint and their relation to weight loss. Parental acceptability was also examined. METHOD: This is a secondary study of a 12-month randomized trial, the RESIST study, which examined the effects of two diets on insulin sensitivity. Participants were 109 obese 10- to 17-year-olds with clinical features of insulin resistance. The program commenced with a 3-month dietary intervention using a structured meal plan, with the addition of an exercise intervention in the next 3 months and followed by a 6 month maintenance period.This paper presents changes in eating behaviors measured by the Eating Pattern Inventory for Children and parent rated diet acceptability during the first 6 months of the trial. As there was no difference between the diets on outcome of interest, both diet groups were combined for analyses. RESULTS: After 6 months, the proportion of participants who reported consuming more in response to external eating cues decreased from 17% to 5% (P = 0.003), whereas non- emotional eating increased from 48% to 65% (p = 0.014). Dietary restraint and parental pressure to eat remained unchanged. A reduction in external eating (rho = 0.36, P < 0.001) and a reduction in dietary restraint (r = 0.26, P = 0.013) were associated with greater weight loss at 3 and 6 months, respectively. Overall this approach was well accepted by parents with 72% of parents considered that their child would be able to follow the meal plan for the longer term. CONCLUSIONS: In the short to medium term, a prescriptive dietary intervention approach is a well-accepted and suitable option for obese adolescents with clinical features of insulin resistance. It may reduce external and emotional eating, led to modest weight loss and did not cause any adverse effect on dietary restraint. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registration Number (ACTRN) 12608000416392 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=83071.

Self-perception and attitude toward physical activity in overweight/obese adolescents: the "martial fitness" study.

This randomized, placebo-exercise controlled trial found that 6-months of Kung Fu training improved enjoyment of physical activity more than the placebo-exercise intervention, while both groups improved perceptions of behavioral conduct and changed strategies for physical activity. Importantly, family support for physical activity declined in subjects who had more visits to health care professionals, which is worrisome, as this represents another risk factor for sedentary behavior in this vulnerable cohort that must be overcome for successful, sustained behavioral change. Programs supporting positive attitudes of both adolescents and their families toward physical activity will be necessary to optimize exercise adoption and adherence as a means to combat the obesity epidemic in childhood and adolescence.

Novel ketamine and zinc treatment for anorexia nervosa and the potential beneficial interactions with the gut microbiome.

Anorexia nervosa (AN) is a severe illness with diverse aetiological and maintaining contributors including neurobiological, metabolic, psychological, and social determining factors. In addition to nutritional recovery, multiple psychological and pharmacological therapies and brain-based stimulations have been explored; however, existing treatments have limited efficacy. This paper outlines a neurobiological model of glutamatergic and γ-aminobutyric acid (GABA)-ergic dysfunction, exacerbated by chronic gut microbiome dysbiosis and zinc depletion at a brain and gut level. The gut microbiome is established early in development, and early exposure to stress and adversity contribute to gut microbial disturbance in AN, early dysregulation to glutamatergic and GABAergic networks, interoceptive impairment, and inhibited caloric harvest from food (e.g., zinc malabsorption, competition for zinc ions between gut bacteria and host). Zinc is a key part of glutamatergic and GABAergic networks, and also affects leptin and gut microbial function; systems dysregulated in AN. Low doses of ketamine in conjunction with zinc, could provide an efficacious combination to act on NMDA receptors and normalise glutamatergic, GABAergic and gut function in AN.

Recruitment challenges and recommendations for adolescent obesity trials.

AIM: To report our experiences with recruiting overweight and obese 13- to 16-year-olds for the Loozit® weight management randomised control trial (RCT) and to identify effective strategies for recruiting adolescents from the community to a treatment trial. METHODS: The Loozit RCT is a two-arm, community-based, lifestyle intervention that aims to evaluate the effect of additional therapeutic contact provided via telephone coaching and electronic communications as an adjunct to the Loozit group programme. Strategic areas that were targeted to recruit adolescents included media, schools, health professionals and community organisations. The programme aimed to recruit a cohort of 12-16 adolescents (body mass index z-score range 1.0-2.5) aged 13-16 years every 3 months over 3 years. Information regarding recruitment and eligibility to participate was initially assessed during a telephone screen. The relative cost effectiveness of recruitment strategies was determined based on recruitment rates and costs including administrative costs and research assistant time. RESULTS: Out of 474 enquiries, 32% resulted in an enrollment to the RCT. Newspaper articles and school newsletters accounted for nearly 60% of enquiries and enrollments and were the most cost-effective recruitment strategies. Common reasons for ineligibility for inclusion in the RCT were adolescents being too young (21%) and parents consenting but adolescents refusing to participate (17%). CONCLUSIONS: The most successful recruitment strategies for the Loozit RCT were local newspapers and school newsletters. Future studies should consider involving a Public Relations department and other potentially cost-effective strategies such as peer recruitment.

Intrinsic Functional Connectivity in the Default Mode Network Differentiates the Combined and Inattentive Attention Deficit Hyperactivity Disorder Types.

Neuroimaging studies have revealed neurobiological differences in ADHD, particularly studies examining connectivity disruption and anatomical network organization. However, the underlying pathophysiology of ADHD types remains elusive as it is unclear whether dysfunctional network connections characterize the underlying clinical symptoms distinguishing ADHD types. Here, we investigated intrinsic functional network connectivity to identify neural signatures that differentiate the combined (ADHD-C) and inattentive (ADHD-I) presentation types. Applying network-based statistical (NBS) and graph theoretical analysis to task-derived intrinsic connectivity data from completed fMRI scans, we evaluated default mode network (DMN) and whole-brain functional network topology in a cohort of 34 ADHD participants (aged 8-17 years) defined using DSM-IV criteria as predominantly inattentive (ADHD-I) type (n = 15) or combined (ADHD-C) type (n = 19), and 39 age and gender-matched typically developing controls. ADHD-C were characterized from ADHD-I by reduced network connectivity differences within the DMN. Additionally, reduced connectivity within the DMN was negatively associated with ADHD-RS hyperactivity-impulsivity subscale score. Compared with controls, ADHD-C but not ADHD-I differed by reduced connectivity within the DMN; inter-network connectivity between the DMN and somatomotor networks; the DMN and limbic networks; and between the somatomotor and cingulo-frontoparietal, with ventral attention and dorsal attention networks. However, graph-theoretical measures did not significantly differ between groups. These findings provide insight into the intrinsic networks underlying phenotypic differences between ADHD types. Furthermore, these intrinsic functional connectomic signatures support neurobiological differences underlying clinical variations in ADHD presentations, specifically reduced within and between functional connectivity of the DMN in the ADHD-C type.

Cognitive and Executive Contributions to Trail-Making Task Performance on Adolescents With and Without Attention Deficit Hyperactivity Disorder.

OBJECTIVE: The trail making task is used to assess executive functioning in ADHD youth, yet has only been validated in adult populations. We compare the relative contributions of various cognitive measures to performance on a trail making task analog, the Switching of Attention (SoA) task, in typically-developing and ADHD adolescents. METHOD: Participants were 160 adolescents with ADHD from the International Study to Predict Optimized Treatment-in ADHD, assessed at pretreatment baseline and 6-week medicated follow-up, and 160 matched typically-developing peers. Attention, processing speed, working memory, impulsivity, and motor speed were assessed using a cognitive battery. RESULTS: Processing speed and working memory significantly contributed to SoA performance in ADHD, regardless of medication status. While medicated, motor speed also underpinned the prediction of most task measures. For typically-developing adolescents, sustained attention and working memory contributed to SoA performance. CONCLUSION: Typically-developing, unmedicated and treated ADHD adolescents recruit different aspects of cognition during SoA completion.

Refeeding in anorexia nervosa: increased safety and efficiency through understanding the pathophysiology of protein calorie malnutrition.

PURPOSE OF REVIEW: This paper reviews recent publications about the physiology associated with adaptation to malnutrition and refeeding (including the refeeding syndrome) and clinical outcomes of refeeding paradigms. RECENT FINDINGS: A number of recent reviews and original publications have highlighted important differences from the assumptions underpinning the current refeeding guidelines for patients with anorexia nervosa. The notion of 'starting low and going slow' with the prescription of daily calories seems unlikely to be important in preventing refeeding syndrome. Recent publications suggest this approach does not necessarily add to safety in the refeeding process but rather the contrary. It typically results in weight loss and protracts hospitalization and nutritional recovery. Rather, the composition of macronutrients, in particular avoiding a high proportion of calories from carbohydrates, appears to be more important than the absolute number of calories. The means of initial refeeding appears increasingly important in this process, particularly following descriptions of postprandial hypoglycemia. SUMMARY: The study supports a review of the current guidelines. Evidence for the use of continuous feeding strategies with less than 40% of calories from carbohydrates is presented. This approach has important implications for the prevention of the refeeding syndrome as well as the safety and efficiency with which refeeding may occur for children and adolescents with anorexia nervosa in hospital.

EEG in adolescent anorexia nervosa: impact of refeeding and weight gain.

OBJECTIVE: To examine resting awake EEG in adolescent AN participants before and after refeeding to determine if EEG abnormalities in Anorexia Nervosa (AN) are reversible. METHOD: In 37 adolescent first admission AN patients and 45 healthy controls, EEG was recorded during short duration "eyes open" and "eyes closed" awake resting conditions. Repeat testing occurred in 28 AN participants after refeeding and subsequent weight gain. RESULTS: In "eyes open," underweight AN participants exhibit reduced relative alpha power and increased beta power in frontal brain regions. A significant increase in alpha, and decrease in beta and delta power was observed within participants after refeeding. In "eyes closed", underweight AN participants had elevated theta in parietal-occipital regions which remained after refeeding. DISCUSSION: EEG abnormalities (reduced alpha/increased beta power) in AN normalizes with refeeding, while increased theta power persists in parietal-occipital regions in an eyes closed context.

Short-term outcomes of community-based adolescent weight management: The Loozit® Study.

BACKGROUND: The Loozit(®) Study is a randomised controlled trial investigating extended support in a 24 month community-based weight management program for overweight to moderately obese, but otherwise healthy, 13 to 16 year olds. METHODS: This pre-post study examines the two month outcomes of the initial Loozit(®) group intervention received by both study arms. Adolescents (n = 151; 48% male) and their parents separately attended seven weekly group sessions focused on lifestyle modification. At baseline and two months, adolescents' anthropometry, blood pressure, and fasted blood sample were assessed. Primary outcomes were two month changes in body mass index (BMI) z-score and waist-to-height-ratio (WHtR). Secondary outcomes included changes in metabolic profile, self-reported dietary intake/patterns, physical and sedentary activities, psychological characteristics and social status. Changes in outcome measures were assessed using paired samples t-tests for continuous variables or McNemar's test for dichotomous categorical variables. RESULTS: Of the 151 adolescents who enrolled, 130 (86%) completed the two month program. Among these 130 adolescents (47% male), there was a statistically significant (P < 0.01) reduction in mean [95% CI] BMI (0.27 kg/m2 [0.41, 0.13]), BMI z-score (0.05 [0.06, 0.03]), WHtR (0.02 [0.03, 0.01]), total cholesterol (0.14 mmol/L [0.24, 0.05]) and low-density lipoprotein cholesterol (0.12 mmol/L [0.21, 0.04]). There were improvements in all psychological measures, the majority of the dietary intake measures, and some physical activities (P < 0.05). Time spent watching TV and participating in non-screen sedentary activities decreased (P < 0.05). CONCLUSIONS: The Loozit(®) program may be a promising option for stabilizing overweight and improving various metabolic factors, psychological functioning and lifestyle behaviors in overweight adolescents in a community setting. TRIAL REGISTRATION: Australian New Zealand Clinical Trials RegistryACTRNO12606000175572.

Impulsivity and Its Relationship With Lisdexamfetamine Dimesylate Treatment in Binge Eating Disorder.

High trait impulsivity is thought to contribute to the sense of loss of control over eating and impulses to binge eat experienced by those with binge eating disorder (BED). Lisdexamfetamine dimesylate (LDX), a drug approved for treatment of moderate to severe BED, has been shown to decrease impulsive features of BED. However, the relationship between LDX-related reductions of binge eating (BE) episodes and impulsivity has not yet been explored. Forty-one adults aged 18-40years with moderate to severe BED completed questionnaires and tasks assessing impulsivity at baseline and after 8weeks of 50-70mg of LDX. Twenty age-matched healthy controls were also assessed at two timepoints for normative comparison. Data were analysed using linear mixed models. BED participants exhibited increased self-reported motor, non-planning, cognitive and food-related impulsivity relative to controls but no differences in objective task-based measures of impulsivity. Food-related and non-planning impulsivity was significantly reduced by LDX, but not to normative levels. Individuals with higher baseline levels of motor and non-planning impulsivity, and loss of control over eating scores experienced the greatest reduction in BE frequency after 8weeks of LDX. Further, there were significant associations between the degree to which subjective loss of control over eating, non-planning impulsivity and BE frequency reduced after 8weeks of LDX. These data suggest that specific subjective measures of impulsivity may be able to predict who will have the greatest benefit from LDX treatment and that reductions in BE frequency may be moderated by concurrent reductions in non-planning impulsivity.

No support for white matter connectivity differences in the combined and inattentive ADHD presentations.

Evidence from functional neuroimaging studies support neural differences between the Attention Deficit Hyperactivity Disorder (ADHD) presentation types. It remains unclear if these neural deficits also manifest at the structural level. We have previously shown that the ADHD combined, and ADHD inattentive types demonstrate differences in graph properties of structural covariance suggesting an underlying difference in neuroanatomical organization. The goal of this study was to examine and validate white matter brain organization between the two subtypes using both scalar and connectivity measures of brain white matter. We used both tract-based spatial statistical (TBSS) and tractography analyses with network-based Statistics (NBS) and graph-theoretical analyses in a cohort of 35 ADHD participants (aged 8-17 years) defined using DSM-IV criteria as combined (ADHD-C) type (n = 19) or as predominantly inattentive (ADHD-I) type (n = 16), and 28 matched neurotypical controls. We performed TBSS analyses on scalar measures of fractional anisotropy (FA), mean (MD), radial (RD), and axial (AD) diffusivity to assess differences in WM between ADHD types and controls. NBS and graph theoretical analysis of whole brain inter-regional tractography examined connectomic differences and brain network organization, respectively. None of the scalar measures significantly differed between ADHD types or relative to controls. Similarly, there were no tractography connectivity differences between the two subtypes and relative to controls using NBS. Global and regional graph measures were also similar between the groups. A single significant finding was observed for nodal degree between the ADHD-C and controls, in the right insula (corrected p = .029). Our result of no white matter differences between the subtypes is consistent with most previous findings. These findings together might suggest that the white matter structural architecture is largely similar between the DSM-based ADHD presentations is similar to the extent of being undetectable with the current cohort size.

Structural brain network topology underpinning ADHD and response to methylphenidate treatment.

Behavioural disturbances in attention deficit hyperactivity disorder (ADHD) are thought to be due to dysfunction of spatially distributed, interconnected neural systems. While there is a fast-growing literature on functional dysconnectivity in ADHD, far less is known about the structural architecture underpinning these disturbances and how it may contribute to ADHD symptomology and treatment prognosis. We applied graph theoretical analyses on diffusion MRI tractography data to produce quantitative measures of global network organisation and local efficiency of network nodes. Support vector machines (SVMs) were used for comparison of multivariate graph measures of 37 children and adolescents with ADHD relative to 26 age and gender matched typically developing children (TDC). We also explored associations between graph measures and functionally-relevant outcomes such as symptom severity and prediction of methylphenidate (MPH) treatment response. We found that multivariate patterns of reduced local efficiency, predominantly in subcortical regions (SC), were able to distinguish between ADHD and TDC groups with 76% accuracy. For treatment prognosis, higher global efficiency, higher local efficiency of the right supramarginal gyrus and multivariate patterns of increased local efficiency across multiple networks at baseline also predicted greater symptom reduction after 6 weeks of MPH treatment. Our findings demonstrate that graph measures of structural topology provide valuable diagnostic and prognostic markers of ADHD, which may aid in mechanistic understanding of this complex disorder.

Emotion brain alterations in anorexia nervosa: a candidate biological marker and implications for treatment.

BACKGROUND: Identification of the biological markers of anorexia nervosa (AN) is crucial for the development of new treatments. We aimed to determine whether AN is associated with disturbances in the nonconscious neural processing of innate signals of emotion and whether these disturbances persist after weight gain. METHODS: In a retest design, 28 adolescent females with AN were tested at first ad not mission to hospital and again after they had gained weight. Matched healthy control participants were tested at the same times. We assessed emotion-elicited event-related potentials (ERPs) during overt and covert presentation of emotion expressions, scores on an emotion-identification behavioural task, and symptom measures. We performed between and within group analyses. RESULTS: Individuals with AN had a marked alteration in ERPs relative to healthy controls. Irrespective of the form of stimulus, early and late ERP componotnents were significantly reduced in AN patients at baseline (when underweight) and on retest (after weight gain), especially in the temporo-occipital regions, suggesting a persistent disruption of the early automatic appraisal of salient emotional signals. LIMITATIONS: This study could have been improved with a longer standardized retest interval. CONCLUSION: There is likely a core, generic disturbance in AN in the early "automatic" neural processing of emotion irrespective of weight or nutritional status. New innovative emotion-based psychologic or pharmacologic treatments targeting these nonconscious processes may prove beneficial.

In first presentation adolescent anorexia nervosa, do cognitive markers of underweight status change with weight gain following a refeeding intervention?

OBJECTIVE: To determine the nature and severity of cognitive functioning impairment in adolescent anorexia nervosa (AN) when underweight and following weight gain. METHOD: In 37 first admission adolescent (12-18 years) AN patients and 45 matched controls, general cognitive functions were assessed at baseline and follow-up using the IntegNeuro-computerized battery. AN participants were tested between days 3 and 10 of their admission when underweight, with retesting conducted after weight restoration. RESULTS: When underweight, AN participants performed more poorly than controls on sensori-motor speed tasks and exhibited a susceptibility to interference, but had superior working memory. Once the weight is restored, individuals significantly improved relative to their own performance. Relative to controls, they were significantly faster on attention and executive function tasks, exhibited superior verbal fluency, working memory, and a significantly superior ability to inhibit well-learnt responses. DISCUSSION: Cognitive impairments in adolescent AN appear to normalize with refeeding and weight gain.